Mansonella perstans and Plasmodium falciparum are among the most common human parasites in Sub-Saharan Africa. They pass through the bloodstream during their life in human host. This study aimed at determining the prevalence, determinants of co-infection with M. perstans and P. falciparum and their possible interaction mechanism. A cross-sectional study was conducted in the Akonolinga Health District among pupils. Each of them was screened for the presence of peripheral blood parasites stages using Giemsa-stained thick and thin blood films. Socio-demographic information was documented using a questionnaire forms. A total of 416 pupils aged 4-15 years (average: 9.17 ± 0.27) were recruited. The overall prevalence was 4.32% and 37.26% for M. perstans and P. falciparum respectively, and prevalence of co-infection was 1.92%. Mean parasite density was 508.7±310.3 (min: 430 - max: 1300) µF/ml for M. perstans and 5240.38±2037.42 (min: 857 – max: 10400) T/μl for P. falciparum. Risks of single infections (aOR = 0.46, P = 0.0264 for M. perstans and aOR = 0.64, P = 0.0432 for P. falciparum) and co-infection (aOR = 0.10, P = 0.0371) were lower for pupils living in urban area than those living in rural area. Parasitemia of both parasite species were similar in single and co-infection situations (P> 0.05). The interaction between these parasites could involve another mechanism than a competition for blood resources. This study outlined that M. perstans and P. falciparum are co-endemic in the Akonolinga health District. In order to guarantee future success in control and eradication of malaria, a bigger attention should be given to M. perstans or other filarial where it is co-endemic with P. falciparum.